The present invention relates to synthetic organic chemistry. In particular, the invention relates to a process for the conversion of a carbon-oxygen bond in a carbonyl compound to a carbon-carbon bond. Such process is of value for the preparation of compounds of interest to the chemical, agrochemical and pharmaceutical industries.
The conversion of a carbonyl group (C.dbd.O) to an olefin (C.dbd.C) is one of the most important synthetic reactions in current use, with numerous applications in research and industry. While a number of methods are known to perform such transformations, these are often restricted to particular types of C.dbd.O groups or in the types of C.dbd.C they can produce.
The most widely used method for the olefination of aldehydes and ketones is the Wittig reaction and its various modifications, including the Horner-Emmons procedure [J. I. G. Cadogan (ed.), "Organophosphorus Reagents in Organic Synthesis," Academic Press, London (1979); H. J. Bestman et al., Top. Cur. Chem. 109:65 (1983)]. While this is a very general method for the synthesis of olefins, it does not work well for readily enolizable ketones, due to the basic nature of the ylides or phosphonate anions used. Moreover, the Wittig reaction gives different products than the expected olefins with esters, lactones or amides.
Several organometallic reagents involving geminal dimetallic derivatives (L.sub.n M.sup.1 --CHR--M.sup.2 L.sub.n) or nucleophilic metallocarbenes (L.sub.n M.dbd.CHR) are also suitable for the preparation of certain types of olefins or enol ethers. These reagents, however, all have a number of structural limitations and experimental drawbacks. Due to the extreme reactivities of many of the reagents involved, such methods are often unsuitable for routine applications, particularly on a large scale. In addition, the reagents typically require the use of special techniques which may be unsuitable for commercial-scale synthetic procedures.
Known methods for the olefination of esters and lactones include the use of the aluminum-titanium complex known as the Tebbe reagent [F. N. Tebbe et al., J. Am. Chem. Soc. 100:3611 (1078); S. H. Pine et al., J. Am. Chem. Soc. 102:3270 (1980); S. H. Pine et al., J. Org. Chem. 50:1212 (1985)]or the related titanocyclobutanes developed by Grubbs [R. H. Grubbs et al., Science 243:907 (1989)]. Due to difficulties in the preparation of homologated variants, however, both of these methods are limited to methylenations. In addition, the Tebbe reagent is also extremely air-sensitive and must be handled under a highly controlled inert atmosphere with sophisticated equipment. Moreover, this reagent is not reliable in its reactions with various carbonyl compounds, and isolation of products prepared using the reagent involves an elaborate aqueous work-up. A further complication when using Tebbe reagent is the presence of residual reactive aluminum by-products; this can affect yields through side-reactions with some of the products. In this respect, the titanocyclobutane may be advantageous, as it is aluminum free. Unfortunately, the titanacyclobutane currently is prepared from the Tebbe reagent, and thus suffers from some of the same disadvantages. Mechanistically, these reagents are believed to olefinate via the highly reactive carbene complex.
Another titanium-based olefination technique involves the use of the RCHBr.sub.2 --Zn--TiCl.sub.4 system to olefinate a variety of carbonyl compounds, including aldehydes, ketones, esters, lactones, silyl esters and thioesters [K. Takai et al., Tetrahedron Lett. 2417 (1978); K. Takai et al., Tetrahedron Lett. 26:5579,5581 (1985); K. Takai et al., Bull. Chem. Soc. Japan, 53:1698 (1980); T. Okazoe et al., J. Org. Chem. 52:4410 (1987); K. Takai, et al., Tetrahedron Lett. 30:211 (1989)]. While this method can be effective for many substrates, it utilizes somewhat drastic conditions and a more cumbersome experimental procedure. In addition, methylenations of esters or lactones are not always efficient with this method. In any event, the use of homologated variants is limited by the availability of particular RCHBr.sub.2 species.
Several other methods have been reported to effect carbonyl olefinations via complexes of zirconium [J. Schwartz et al., Pure App. Chem. 60:65 (1988); J. M. Tour et al., Tetrahedron Lett. 30:3927 (1989)], tantalum [Schrock, R. R., Acc. Chem. Res. 12:98 (1979)] and aluminum [A. M. Piotrowski et al., J. Org. Chem. 53:2829 (1988)]. All of these methods are apparently of a narrow applicability and are limited only to certain substitution patterns. Moreover, these reaction schemes use very costly or highly toxic reagents.
Accordingly, there is a need in the art for a general, practical and convenient method for the conversion of a carbon-oxygen bond to a carbon-carbon bond via olefination of a variety of carbony compounds, particularly esters, lactones, amides and lactams.
It is an object of the present invention to provide a practical and effective method for the conversion of a carbon-oxygen bond to a carbon-carbon bond via conversion of a carbonyl compound to the corresponding olefin, which method obviates the disadvantages attendant to the methods of the prior art.